Motor neuron disease is a neurodegenerative disease of unknown etiology, primarily implicating cerebral cortex, brain stem and spinal motor neuron, including amyotrophic lateral sclerosis (ALS), progressive muscular atrophy, progressive bulbar paralysis and primary lateral sclerosis. Wherein, ALS is the most common type of motor neuron diseases. The onset age of ALS is between 50˜60 years old, and the morbidity is 2/100000, which is characterized by the selective death of upper and lower motor neurons, resulting in progressive muscular atrophy, inertia and stiffness. The median survival time from the onset of ALS to death is 39 months, most patients generally die from respiratory failure in 3˜5 years. About 5˜10% of the familial ALSs are usually autosomal dominant;90˜95% of the ALS cases are sporadic ALS (Nat Rev Neurosci 2001; 2: 806-819;Annu Rev Neurosci 2004; 27: 723-749).
About 20% of the familial ALSs are caused by the genetic mutation of the Cu/Zn superoxide dismutase (SOD1). Due to the similarities on the clinical manifestations of sporadic and familial ALSs, it is set forth that the potential mechanism of the familial ALS is useful for studying two forms of ALS. Hence, the transgenic mice carrying human mutant SOD1 opens the field of study on the familial ALS pathology (Neuron 2006; 52:39-59). It is indicated in recent research that there are abnormal SOD1 proteins in the spinal cord tissues from sporadic ALS and familial ALS patients, implying that SOD1 may play a role in both forms of ALS diseases (Annu Rev Neurosci 2004; 27: 723-749). In addition, it is found latest that there are RNA metabolism protein TDP-43genetic mutations in familial ALS autosome, meanwhile there are also pathological changes of TDP-43 proteins in most sporadic ALS patients, implying that TDP-43 may be of significant importance in understanding sporadic and familial ALSs (Proc Natl Acad Sci USA 2007;104: 12524-12529). The pathogenesis of ALS is complex, and the current biological hypothesis includes oxidative damage, accumulation of aggregates in cells, mitochondrial dysfunction, deficiency of axonal transport, lack of growth factor, colloid cell pathology and glutamate excitotoxicity (Ann Neurol. 2009 Jan; 65Suppl 1:S3-9).
3-methyl-1-phenyl-2-pyrazolin-5-one (edaravone), as a new potent free-radical scavenger, may scavenge hydroxyl radical (OH), nitric oxide radical (NO.), peroxynitrite ion (ONOO—) (Chem Pharm Bull 2004, 52(2):186-91; Redox Rep. 2002, 7(4): 219-22; J Pharmacol Exp Ther. 2007, 322 (1): 274-81), inhibit cell peroxidative damage; as an effective neuron protective agent (free-radical scavenger), may have advantages of wide distribution, short half-life, safe and low toxicity and is an effective first-line therapeutic drug in clinical ischemic stroke (Guidelines for the diagnosis and treatment of acute ischemic stroke in China, 2010). Edaravone has favorable neuroprotective effects in animal models with neurodegenerative diseases, such as animal models with 0 amyloid proteins (Aβ) injected in lateral ventricle and with streptozotocin (STZ) injected in lateral ventricle (Biomed Res Int. 2014;2014:370368; Neurotoxicology. 2013, 38:136-45). In addition, edaravone is capable of slowing the progression of the symptoms in mutant SOD1 G93A mice ALS and the degeneration of neuron (Exp Neurol. 2008, 213(2):448-55). Patent W02005/075434 discloses the use of 3-methyl-1-phenyl-2-pyrazolin-5-one in treating amyotrophic lateral sclerosis. However, it is suggested in a clinical phase-III study that the score of the amyotrophic lateral sclerosis Functional Rating Scale-Revised (ALSFRS-R) in edaravone group decreased less than the placebo group, there was no significant difference; the study results of clinical trials have not reached the primary endpoint (NCT00330681; Amyotroph Lateral Scler Frontotemporal Degener. 2014 Dec;15(7-8):610-7). Another clinical phase-III experiment (NCT01492686) is ongoing, but has not been recruited.
Borneol is divided into synthetic borneol and natural borneol. Synthetic borneol contains isoborneol, while natural borneol contains no isoborneol. Natural borneol is also known as 2-camphol. It is suggested in a study that borneol is capable of improving intestinal absorption (AAPS Pharm Sci Tech. 2011 Dec;12(4):1044-9), blood-brain barrier (J Asian Nat Prod Res. 2014, 16(6): 648-57; J Ethnopharmacol. 2015, 162:270-7) and corneal permeability (Pharmazie.2006, 61(9):783-8), neuroprotective effect (Neuroscience. 2011, 176:408-19;Eur JPharmacol. 2014, 740:522-31), anti-inflammation (Inflammation. 2014, 37(4):1148-57), antioxidation and protecting DNA injuries (J Agric Food Chem. 2014, 62(28):6632-9), enhancing GABA receptor functions (Biochem Pharmacol. 2005, 69(7):1101-11), and also improving rat coagulation functions, antithrombotic activities (Am J Chin Med. 2008; 36(4):719-27).
The clinical III experimental study on the composition of 3-methyl-1-phenyl-2-pyrazolin-5-one and natural borneol with a mass ratio of 4:1 being useful for treating ischemic stroke has been developed in China. It was suggested in the preclinical animal experiments that the composition with a mass ratio of 4:1˜1:1 can synergistically reduce the area of cerebral infarction (Patent CN 101848711 B), the composition with a mass ratio of 4:1˜2:1 can synergistically reduce the mortality of animals with sepsis (Patent 201310474253.8).
Based on the prior art, it is unanticipated whether the composition of 3-methyl-1-phenyl-2-pyrazolin-5-one and borneol can be used in treating amyotrophic lateral sclerosis and related disorders, and it is not determinable whether the composition of 3-methyl-1-phenyl-2-pyrazolin-5-one and borneol with the current mass ratio of 4:1 has synergetic effects.